The present disclosure provides the design and synthesis of novel steroidal compounds that cause down-regulation of the androgen receptor (AR), both full length and splice variant. The compounds are potential agents for the treatment of all forms of prostate cancer and other diseases that depend on functional AR.
Compelling laboratory and clinical evidences strongly indicates that incurable castration-resistant prostate cancer (CRPC) remains dependent on functional androgen receptor (AR), AR-mediated processes, and the availability of intra-prostatic intracellular androgens. Unlike early stage prostate cancer (ESPC), CRCP is not responsive to classical AR antagonist, [hydroxyflutamide (1) or bicalutamide (2); FIG. 1] or androgen deprivation therapy (luteinizing hormone-releasing hormone agonists/antagonists). Therefore, recent strategies have focused on the development of more potent androgen synthesis inhibitors or AR antagonists. These research efforts have led to ongoing clinical evaluations/approvals of three potent CYP17 inhibitors, abiraterone acetate (Zytiga, 3a), TAK-700 (Orteronel, 4) and VN/124-1 (TOK-001 or galeterone, 5), and two potent AR antagonists, MDV3100 (enzalutamide, 6) and ARN-509 (7). The chemical structures of these clinical compounds are presented in FIG. 1.
Despite the substantial clinical efficacy with Zytiga in patients with post-docetaxel CRPC, resistance to this therapy has already been reported. Resistance to MDV3100 treatment has also been reported. Reactivation of AR signaling following Zytiga or MDV3100 treatment might occur by several mechanisms, prominent of which is a switching of transcription program under the control of AR signaling. Indeed, it may not be possible to inhibit the new AR-regulated transcription program by currently available therapies and some of the promising agents in clinical development. If so, substantial down-regulation of AR (full length and truncated forms) expression would be a promising strategy for future studies.
Herein, we report several novel compounds which exhibit the abilities to induce AR (full length and truncated) ablation at low micromolar concentrations and with improved anti-proliferative (AP) activities. This study expands the current understanding of the optimal pharmacophore requirements for AR degradation/down-regulator (ARD) activity and their capabilities in regulating the activity of the AR (i.e., AR inactivation).